Tri-sulfa aluminum salts



United States Patent ()fihce 2,776,97fi Patented Jan. 8, 1957 TRI-SULFA ALUMINUM SALTS;

Carl J. Lintner, Jr., Kalamazoo Township, Kalamazoo County, Mich., assignor to The Upjohn Company, Kalamazoo, MiclL, a corporation of Michigan No Drawing. Application February 1, 1956, Serial No., 562,650

7 Claims. (Cl. 260-43955) More particular types of utility may be illustrated by that possessed by sulfacetamide and sulfamethazine.v Sulfacetamide is adyocatedfor the treatment. of urinary tract infections. It is active against Staphylococcus aureus, Streptococcus fecali Escherichia coli, Aerobacter aerogenes and Proteus ammoniae. Gonorrhea has responded clinically. At least one investigator concluded .that it was preferable to-othersulfonamides as a urinary antiseptic on the basis of pharmacological properties and toxic effects. It has beenused effectively and safely for children and during pregnancy. Another investigator used it for meningoeoccus meningitis. Sulfamethazine is useful for hemolytic streptococcic, pneumococcic, meningococcic, staphylococcic and certain urinary tract infections. I

In addition to theforegoingindividualuses, these sulfonamides in the form of the novel compounds ofthe present invention, are advantageously used in combination with antibiotics, such as penicillin, neomycin, streptomycin, erythromycin, bacitracin, circulin, aureomycin, chloromycetin, terramycin combinations of the foregoing, or the like. The novel compounds of the present invention are alsofuseful in compositions with thefollowing: analgesics and antipyreti'cs, such as aspirin, phenacetin, salicylamide, acetylparaaminophenol, or the like; bronchodilators, such as ephedrine, methoxyphenamine hydrochloride, or the like; antihistamines, such as diphenhydramine hydrochloride, prophenpyridamine maleate, pyrilamine maleate, tripelennamine citrate, or the like; antispasmo'dics, such as methantheline bromide, scopolamine methyl bromide, or the like; sedatives, such as barbiturates, carbromal, or the like; diuretics, such as sodium mercurophylline, aminophylline, or the. like; urinary antiseptics, such as methenamine, methenamine mandelate, or the like; and other adjuvants or synergists.

Inview of these important uses and the ease of administration which accrues to the manufacture of oral preparations, the preparation of palatable tablets or liquid preparations containing one or more of the above-named objectionable tasting sulfonamides has been a serious problemto. the pharmaceutical industry. Their obnoxious taste, generallycharacterized as bitter or astringent with a lingering after-taste, has been diflicult to disguise.

" It is therefore an object of this invention to provide novel salts of bad tasting sulfonamides, such as sulfamethazine, sulfacetamide, sulfisoxazole, sulfadimetine,

and sulfathiazole, which salts are particularly well-suited for oral administration because, of their tastelessness.

It isalso an object of this invention to provide novel aluminum salts of bad tasting sulfonamides, such as sulfamethazine, sul'facetamide, sulfisoxazol'e, sulfadimetine, and sulfathiazole, which salts can be effi'ciently absorbed from the alimentary tract.

Another object is to provide novel aluminum salts of bad-tasting sulfonamides suchv as sulfamethazine, sulfacetamide, sulfisoxazole, sulf'adimetine, and sulfathiazole which salts, because of more gradual absorption from the alimentary tract, result in more prolonged sulfonamide blood levels and greater therapeutic effectiveness.

Still another object'is to provide novel aluminum salts of unpleasant-tasting sulfonamides, such as, sulfamethazine, sulfacetamide, sulfi'soxazole, sulfadimetine, and sulfathiazole, which salts, also because. of more gradual absorption from the alimentary tract, result in fewer un- I desirable sidereactions such as nausea. and vomiting.

Other objects will be apparentto one skilled in the art to which the invention pertains.

The foregoing and additional objects have been accomplished by the provision of aluminum trisulfonamide salts which have the following formula:

Rt v ALB:

wherein R1 is a radical selected from the group con sisting of sulfacetamide, sulfalnethazine, sulfisoxazole, sulfadimetine, and sulfathi'azole, and R2 and Rs are radicals selected from the group consisting of sulfamethazine, sulfacetamid'e, sulfisoxazole,'-sulfamerazine, sulfadiazine, 'sulfapyridine, sulfathiazole, sulfaguanidine, and sulfadimetine. a

In general, these sparingly soluble aluminum trisulfonamide salts are'prepared by mixing together aqueous solutions. containing-the desired number of equivalents of soluble salts of bad-tasting para-aminobenzenesulfonam id'es'including at least one equivalent ofa watersoluble salt of a member selected'from the group consisting of. sulfamethazine, sulfacetamide, sulfisoxazole, sulfadimetine, and sulfathiazole, such as the sodium or potassium salt thereof, with a water-soluble aluminum salt, such as aluminum sulfate, aluminum chloride, or alum. The precipitate of aluminum tris-ulfonamide is col- 'lected by filtration, washed with water and dried. The

reaction is operative at any temperature between about zero degrees centigrade and about degrees Centigrade, although temperatures between about zero degrees centigrade and room temperature are preferred. Although water is the preferred solvent for this reaction, any solvent predominantly aqueous such as one consisting of a major portion of Water and a minor portion of water-miscible lower alcohols or glyeols is operative.

In one embodiment of the invention, a mixture of two or more di'lferent sulf'onamides, including at least one bad-tasting sulfonamid'e such as sulfamethazine, sulfacetamide, sulfisoxazole,sulfadimetine, or sulfathiazole, can be used in the reaction to obtain an aluminum sulfonamide complex in which, for example, one atom of aluminum is bound to one molecule of sulfamethazine, one molecule'of sulfacetamide and one molecule of sulfadiazine; or, for example, one atom of aluminum is bound to two molecules. ofv sulfamethazine and one molecule of sulfacetamide; or, for-example, one atom of aluminum is bound to three molecules of three dif- Experiment shows that any sulfonamide radical is capable of combining with aluminum to form a waterinsoluble salt. The present invention encompasses aluminum trisulfonamide salts of the following formula:

wherein R1 is a radical selected from the group consisting of sulfacetamide, sulfamethazine, sulfisoxazole, sulfadimetine, and sulfathiazole, and R2 and R3 are radicals selected from the group consisting of sulfamethazine, sulfacetamide, sulfisoxazole, sulfamerazine, sulfadiazine, sulfapyridine, sulfathiazole, sulfaguanidine, and sulfadimetine.

The present invention also encompasses aluminum trisulfonamide salts in which the three valences of the aluminum are satisfied by the same member of the group consisting of sulfacetamide, sulfamethazine, sulfisoxazole, sulfadimetine, and sulfathiazole; for example, aluminum trisulfacetamide, aluminum trisulfamethazine, aluminum trisulfisoxazole, aluminum trisulfadimetine, and aluminum trisulfathiazole.

The term sulfonamide, as used herein, includes sulfanilamide and the various sulfanilamide derivatives obtained by replacing one of the hydrogen atoms on the amido nitrogen or N atom by another group. Dibasic acid substituents on either nitrogen of the sulfanilamide are inoperative for the purpose of the present invention since they may lead to the interaction of one sulfonamide with two atoms of aluminum, or with two valences of one atom of aluminum. The sulfonamides of the invention preferably have an unsubstituted amino group, i. e. two hydrogen atoms on the N atom. Examples of the preferred sulfonamides of this invention include sulfamethazine, sulfacetamide, sulfisoxazole, sulfamerazine, sulfadiazine, sulfapyridine, sulfathiazole, sulfaguanidine, sulfadimetine, and the like.

The following examples are illustrative of the process and products of this invention and are not to be construed as limiting.

Example I.Aluminum trisulfamethazine A12 (S04) 3 18H2O+ 6NaZ- 2AlZ3 3Na2SO4+ 181-120) where Z stands for a sulfamethazine radical having the following structural formula:

H l CHI-O (3-011:

A12(SO4)3' 181-120 was dissolved in two milliliters of water. The aluminum sulfate solution was added with constant stirring to the sodium sulfamethazine solution at room temperature. A precipitate of aluminum trisulfamethazine formed immediately, was recovered by filtration using reduced pressure and subsequently washed twice with one-milliliter portions of water. After the precipitate hadbeen removed from the filter funnel and placed ina small evaporating dish, the precipitate was dried in a hot air oven at forty degrees centigrade.

The dried aluminum trisulfamethazine was white in color. No melting point could be determined. It was tasteless. The product, which is amorphous when observed under a polarizing microscope, weighed 1.70 grams (99 percent of theory). The official assay method for sulfonamides of the United States Pharmacopeia (sodium nitrate method) indicated 87.1 percent sulfamethazine.

Example 2.-Aluminum trisulfacetamidc Alz (SO93 18H20+ 6NaY- 2AlY3+ 3Na2SO4-l-18H2O wherein Y stands for a sulfacetamide radical having the following structural formula:

NaY was formed as follows:

HY-l-NaOH-eNaY-l-HzO Analytical grade sodium hydroxide (10.56 grams; 0.264 mole) was dissolved in 75 milliliters of water and to this solution 56.56 grams (0.264 mole) of sulfacetamide was added. The mixture was shaken until sodium sulfacetamide had formed as evidenced by formation of a clear solution. Hydrous aluminum sulfate,

(26.65 grams; 0.040 mole), was dissolved in 35 milliliters of water and the aluminum sulfate solution was then added rapidly with rapid stirring to the sodium sulfacetamide solution. A white precipitate of aluminum trisulfacetamide was formed. The precipitate was collected on a fritted glass filter, washed twice with successive ten-milliliter portions of distilled water, and finally dried in a hot air oven at forty degrees centigrade.

The dried aluminum trisulfacetamide was white in color. 'No melting point could be determined. It was completely tasteless. The official assay method for sulfonamides of the United States Pharmacopeia (sodium nitrate method) indicated 78.84 percent sulfacetamide.

Example 3.Aluminum monosulfz'zmethazine monosulfacetamide monosulfadiazine ZAJ Y 3NazSO4 181110 wherein Z is the sulfamethazine radical, Y is the sulfacetamide radical and X is the sulfadiazine radical.

Sodium sulfamethazine (33.03 grams; 0.11 mole), so dium sulfacetamide (25.98 grams; 0.11 mole) and sodium sulfadiazine (29.95 grams; 0.11 mole) were dissolved in ninety milliliters of water. Hydrous aluminum sulfate, Alz(SO4)3.18HzO (33.32 grams; 0.05 mole), was dissolved in forty milliliters of water. The aluminum sulfate solution was added to the solution of the sulfonamides rapidly with constant stirring. A precipitate of aluminum monosulfamethazine monosulfacetamide monosulfadiazine formed immediately. The precipitate was collected on a fritted glass funnel, washed twice with successive twentymilliliter portions of water, and finally dried at forty degrees centigrade in a hot air oven. It was completely tasteless. The United States Pharmacopeia .assay indicated 85.5 percent of total sulfonamides in the product using the average of the molecular Weights of the three sulfonamides present.

Example 4.-Allm1inum trisulfisoxazole In the manner shown in Example 1, aluminum trisulfisoxazole is prepared by reacting sodium sulfisoxazole with hydrous aluminum sulfate in a molar ratio of about three to about onehalf. The product proved to be tasteless.

Example 5 .-Aluminum Irisulfadimetine In the manner shown in Example 1, aluminum trisulfadimetine is prepared by reacting sodium sulfadi- Inetine with hydrous aluminum sulfate in a molar ratio weave of about three rto about one-half. product proved to be tasteless. j v

Example 6.-Aluminani trisulfathiazole In the manner shown in Example I, aluminum trisulfathiazole is prepared by reacting sodium sul'fathiazole with hydrous aluminum sulfate in a molar relation of about three to about one-half. The product proved to be tasteless. I I I Example 7.Aluminum vnionos ulfaalz'metin e monosulfacetamide monosalfamraz'ine I In the mannershown in Example 3', aluminum mono sulfadimetine monosulfacetamide monosulfamerazine is prepared by reacting aluminum chloride with sodium sulfadimetine, potassium sulfacetamide, and potassium sul- V famerazine, the reactants being used inabout equimolar quantities. The product proved to be tasteless.

Example 8.Aluminum monosulfisoxazole disulfagaanidine In the manner shown in Example 3, aluminum monosulfisoxazole disulfagnanidine is prepared by 1 reacting aluminum chloride with sodium sulfisoxazole and potassium sulfaguanidine in the molar ratio of about one to about one to about two. The product proved to be tasteless.

Example 9.Aluminum 'disalfathiazole monosulfanilamide In the manner shown in Example 3, aluminum disulfathiazole monosulfanilamide is prepared by reacting hydrous aluminum sulfate with potassium sulfathiazole and sodium sulfaniliamide in the molar ratio of about onehalf to about two to about one. The product proved to be tasteless.

Example 10.Aluminum disulfamethazinc monosulfathiazole In the manner shown in Example 3, aluminum disulfamethazine monosulfathiazole is prepared by reacting hydrous aluminum sulfate with potassium sulfamethazine and sodium sulfathiazolein the molar ratio of about onehalf to about two to about one. The product proved to be tasteless.

Example 11.Aluminum monosulfadiazine monosalfamerazine monosulfamethazine v In the manner shown in Example 3, aluminum monosulfadiazine monosulfamerazine monosulfamethazine is prepared by reacting aluminum chloride with sodium sulfadiazine, sodium sulfamerazine and sodium sulfamethazine, the reactants being used in about equimolar amounts.

The product proved to be tasteless.

Example 12.Aluminum monosulfadiazine monosulfamerazine monosulfathiazole In the manner shown in Example 3, aluminum monosulfadiazine monosulfamerazine monosulfathiazole is pre- Aluminum trisulfisoxazole Aluminum trisulfadimetine Aluminum trisulfathiazole Aluminum trisulfamethazine Aluminum trisulfacetamide Aluminum disulfisoxazole monosulfadimetine a 6 Aluminum disulfisoxazole monosulfathiazole Aluminum disulfisoxazole monosulfamethazlne Aluminum disulfisoxazole monosulfacetamide Aluminum disulfisoxazole monosulfamerazine Aluminum disulfisoxazole monosulfadiazine Aluminum disulfadimetine monosulfisoxazole Aluminum disulfadimetine monosulfathiazole Aluminum disulfadimetine monosulfamethazine Aluminum disul fadimetinemonosulfacetarnide Aluminum disulfadimetine monosulfamerazine' Aluminum disulfadimetine monosulfadiazine Aluminum disulfathiazole monosulfisoxazole Aluminum disulfathiazole monosulfadimetine Aluminum disulfathiazole monosulfamethazine Aluminum disulfathiazole monosulfacetami'de Aluminum disulfathiazole monosulfamerazine Aluminum disulfathiazole monosulfadiazine Aluminum disulfamethazine monosulfisoxazole Aluminum disulfamethazine monosulfadimetine Aluminum disulfamethazine monosulfathiazole Aluminum disulfamethazine monosulfacetamide Aluminum disulfamethazine monosulfamerazine Aluminum disulfamethazine monosulfadiazine Aluminum disulfacetamide monosulfisoxazole Aluminum disulfacetamide monosulfadimetine Aluminum disulfacetamide monosulfathiazole Aluminum disulfacetamide monosulfarnethazine Aluminum disulfacetamide monosulfamerazine Aluminum disulfacetamide monosulfadiazine Aluminum disulfamerazine monosulfisoxazole Aluminum disulfamerazine monosulfadimetine Aluminum disulfamerazine monosulfathiazole Aluminum disulfam-erazine monosulfamethazine Aluminum disulfamerazine monosulfacetamide Aluminum disulfadiazine monosulfisoxazole Aluminum disulfadiazine monosulfadimetine Aluminum disulfadiazine monosulfathiazole Aluminum disulfadiazine monosulfamethazine Aluminum disulfadiazine monosulfacetarnide Aluminum monosulfathiazole monosulfamethazine monosulfacetamide Aluminum monosulfamethazine monosulfacetamide monosulfamerazine Aluminum monosulfacetamide monosulfamerazine monosulfadiazine Aluminum monosulfamerazine monosulfadiazine monosulfisoxazole Aluminum monosulfadiazine monosulfisoxazole monosulfadimetin-e Aluminum monosulfamethazine monosulfamerazine monosulfisoxazole Aluminum monosulfadimetine monosulfathaziole sulfacetamide Aluminum monosulfathiazole monosulfacetamide sulfadiazine Aluminum monosulfacetamide monosulfadiazine sulfadimetine Aluminum monosulfadiazine monosulfadimetine sulfathiazole Aluminum monosulfisoxazole monosulfathiazole sulfamerazine Aluminum monosulfathiazole monosulfamerazine sulfadimetine Aluminum monosulfamerazine monosulfadimetine monosulfamethazine Aluminum monosulfadimetine monosulfamethazine mon osulfadiazine IIIOIIO- IllOIlO- Aluminum monosulfacetamide monosulfisoxazole monosulfathiazole It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art,

' and the invention is therefore to be limited only by th scope of the appended claims.

mono- V lIlOl'lO- V I claim: i V 1. An aluminum trisulfonamide salt having the following formula:

wherein R1 is a radical selected from the group consisting of sulfacetamide, sulfamethazine, sulfisoxazole, sulfadimetine, and sulfathiazole and R2 and R: are radicals selected from the group consisting of sulfamethazine, sulfacetamide, sulfisoxazole, sulfamerazine, sulfadiazine, sulfapyridine, sulfathiazole, sulfaguanidine, and sulfadimetine.

2. Aluminum trisulfacetamide.

3. Aluminum trisulfamethazine.

4. Aluminum disulfamethaz'ine monosulfathiazole.

5. Aluminum monosulfamethazinc monosulfacetamidc monosulfadiazine 6; Aluminum monosulfadiazine monosulfamcrazinc monosulfarnethazinc. t

7. A process for producing an aluminum trisulionamide salt which comprises mixing an aqueous aluminum salt solution with an aqueous sulfonamide salt solution containing at least one sulfonamide selected from the group consisting of sulfacetamide, sulfamethazine, sulfisoxazole, sulfadimetine, and sulfathiazole, and separating the thus-produced aluminum trisulfonamide salt.

No references cited. 

1. AN ALUMINUM TRISULFONAMIDE SALT HAVING THE FOLLOWING FORMULA: 